Each year, nearly 6,000 new cases of chronic myeloid leukemia (CML) are diagnosed in the United States (Cancer.org. (2013) Available from: cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key-statistics). The fusion oncoprotein Bcr-Abl, the product of t(9;22)(q34;q11), is the causative agent of chronic myeloid leukemia (CML) (Nowell, P. C. (1962) Blut. 8, 65-66; Bartram, C. R., et al. (1983) Nature 306, 277-280; Ren, R. (2002) Oncogene 21, 8629-8642). BCR-ABL1 is a constitutively active tyrosine kinase and the target of small molecule therapeutics for the disease including the first inhibitor of its kind, imatinib (Druker, B. J., et al. (1996) Nat. Med. 2, 561-566; Naldini, L., et al. (1986) Mol. Cell Biol. 6, 1803-1811; Evans, J. P., et al. (1987) Leukemia 1, 524-525). Overall, imatinib has displayed considerable efficacy in CML, with high rates of complete hematologic (CHR) and cytogenetic response (CCyR) that have translated into improved progression-free and overall survival compared to non-TKI therapies (Hanfstein, B., et al. (2012) Leukemia 26:2096-2102; Sawyers, C. L., et al. (2002) Blood 99, 3530-3539; Hochhaus, A., et al. (2007) Blood 109, 2303-2309; Le Coutre, P., et al. (2008) Blood 111, 1834-1839; Hehlmann, R., et al. (1993) Blood 82, 398-407; Ohnishi, K., et al. (1995) Blood 86, 906-916). Although many imatinib responses are durable, some patients acquire kinase domain mutations that confer BCR-ABL1-dependent resistance and are associated with clinical relapse (Branford, S., et al. (2003) Blood 102, 276-283).
To overcome this type of resistance, second-generation TKIs dasatinib, nilotinib, and bosutinib, and most recently the pan-BCR-ABL inhibitor ponatinib, were developed Cassuto, O., et al. (2012) Oncotarget 3, 1557-1565). Second generation TKIs are active in imatinib-resistant patients with or without BCR-ABL1 mutations, but have no activity in patients with the T315I mutation in the gatekeeper position of the kinase (O'Brien, S., et al. (2011) J. Natl. Compr. Canc. Netw. 9 Suppl. 2:S1-25; Mian, A. A., et al. (2009) Leukemia 23, 614-1621). In contrast to the first and second generation TKIs, ponatinib is effective against the T315I mutant, representing a major therapeutic breakthrough (Burke, A. C., et al. (2011) Expert Opin. Emerg. Drugs 16, 85-103). Thus far no single mutation has been shown to confer resistance to ponatinib, but multiple mutations in the same BCR-ABL1 molecule, referred to as compound mutations, can confer resistance to ponatinib in vitro and possibly in vivo.
Second and third generation tyrosine kinase inhibitors (nilotinib, dasatinib, bosutinib, ponatinib) have been developed to cover a more broad range of Bcr-Abl kinase domain mutations, leading to greater success in CML therapy and in all cases showing higher potency (O'Hare, T., et al. (2012) Nat. Rev. Cancer 12, 513-526). This broader range of coverage and enhanced potency, especially with the third generation ponatinib, also leads to inhibition of other tyrosine kinases, namely FLT3, KIT, and VEGFR, to name a few (Garner, A. P., et al. (2013) AACR Annual Meeting Abstracts; Gozgit, J. M., et al. (2011) Mol. Cancer Ther. 10, 1028-1035). Inhibition of off-target kinases in many patient cases has led to the appearance of toxic side effects, including thrombocytopenia, rash, arthralgia, and serious blood clotting (Neelakantan, P., et al. (2012) Haematologica 97, 1444; Cortes, J. E., et al. (2012) N Engl. J. Med. 367, 2075-2088). In fact, the recently FDA-approved ponatinib (Iclusig), the first TKI able to target the long sought-after “gate-keeper” T315I point mutation in Bcr-Abl, had been in a Phase III trial for first-line therapy in CML patients. This trial has since been discontinued due to the serious side effects seen in nearly 12% of patients (Inman, S. (2013) Late-stage ponatinib study discontinued), presumably due to its broad specificity and potency, and further resulting in the complete withdrawal of ponatinib from the market as of October 2013 (Mulcahy, N. (2013) Leukemia drug ponatinib (Iclusig) pulled from market). In addition to showing toxic side effects, consecutive treatment with multiple TKIs has shown to allow for compound mutations, or multiple Bcr-Abl point mutations in a single molecule, to arise (Eide, C. A., et al. (2011) Blood (ASH Annual Meeting Abstracts) 118, 1416). Despite certain TKI success against a variety of single point mutations, many of these compound mutations still show a high level of resistance against all currently available TKIs, leaving no treatment for this increasing subset of patients (Khorashad, J. S., et al. (2013) Blood 121, 489-498).
Rational therapy of CML has thus far focused on targeting the BCR-ABL1 catalytic site, but as described above, kinase domain mutations that impair or block drug binding limit the scope of this approach (Zhang, J., et al. (2009) Nat. Rev. Cancer 9, 28-39). Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event. The domain responsible and necessary for oligomerization is the coiled-coil (CC) domain in the N-terminus of BCR, and this domain has been shown to be critically important for BCR-ABL1. In order to aberrantly activate the downstream signaling characteristic of this disease, Bcr-Abl must homo-oligomerize via a coiled-coil domain located at its N-terminus (Hazlehurst, L. A., et al. (2009) Cancer Control 16, 100-107; Zhao, X., et al. (2002) Nat. Struct. Biol. 9, 117-120). Removing this domain, or simply disrupting oligomerization, eliminates the oncogenic activity of Bcr-Abl (McWhirter, et al. (1993) Mol. Cell Biol. 13:7587-95; and Dixon, A. S., et al., (2011) J. Biol. Chem. 286:27751-60). Thus, this domain could thus represent an alternative target (Zhao, X., et al. (2002) Nat. Struct. Biol. 9, 117-120; McWhirter, J. R., et al. (1993) Mol. Cell Biol. 13, 7587-7595). A peptidomemetic to block dimerization were explored by several groups. For example, Ruthardt et al. reported that introduction of a peptidomemetic of helix α2 of the dimerization region of the coiled-coil of BCR reduced BCR-ABL1 phosphorylation and inhibited the proliferation of cells expressing wild-type and mutant BCR-ABL1 variants (Beissert, T., et al. (2008) Int. J. Cancer 122, 2744-2752). However, the isolated wild-type helix 2 alone was inactive in cells expressing the T315I mutant (Beissert, T., et al. (2008) Int. J. Cancer 122, 2744-2752; Mian, A. A., et al. (2009) Leukemia 23, 2242-2247).
Thus, there remains a need for effective, safe, and selective Bcr-Abl inhibitors, particularly Bcr-Abl inhibitors that do not target the catalytic kinase domain of the protein and that are effective against mutant forms of Bcr-Abl or cancers that are refractory to treatment with currently available Bcr-Abl inhibitors. Therefore, there remains a need for methods and compositions that overcome these deficiencies and that effectively provide Bcr-Abl inhibitors.